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- Title
Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease.
- Authors
Tate, Barbara; McKee, Timothy D.; Loureiro, Robyn M. B.; Dumin, Jo Ann; Xia, Weiming; Pojasek, Kevin; Austin, Wesley F.; Fuller, Nathan O.; Hubbs, Jed L.; Shen, Ruichao; Jonker, Jeff; Ives, Jeff; Bronk, Brian S.
- Abstract
The AmyloidHypothesis states that the cascade of events associated with Alzheimer's disease (AD)--formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline--are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme hasmultiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon ϵcleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ϵcleavage of APP and other substrates while decreasing the production of Aβ42.Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ϵ cleavage of all substrates while shifting APP cleavage from Aβ42 and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity.
- Subjects
THERAPEUTIC use of enzymes; ALZHEIMER'S disease; ANIMAL experimentation; BIOLOGICAL models; RESEARCH methodology; MICE; TISSUE culture; DRUG development; IN vitro studies
- Publication
International Journal of Alzheimer's Disease, 2012, p1
- ISSN
2090-0252
- Publication type
Article
- DOI
10.1155/2012/210756